Despite the rapidly increasing capacity to sequence human genomes, our incomplete ability to read and interpret the information content in genomes and epigenomes remain a central challenge. A comprehensive set of regulatory events across a genome - the regulome - is needed to make full use of genomic information, but is currently out of reach for practically all clinical applications and many biological systems The proposed Center will develop technologies that greatly increase the sensitivity, speed, and comprehensiveness of understanding genome regulation. We will develop new technologies to interrogate the transactions between the genome and regulatory factors, such as proteins and noncoding RNAs, and integrate variations in DNA sequences and chromatin states over time and across individuals. Novel molecular engineering and biosensor strategies are deployed to encapsulate the desired complex DNA transformations into the probe system, such that the probe system can be directly used on very small human clinical samples and capture genome-wide information in one or two steps. These technologies will be applied to clinical samples and workflows in real time to exercise their robustness and reveal for the first time epigenomic dynamics of human diseases during progression and treatment. These technologies will be broadly applicable to many biomedical investigations, and the Center will disseminate the technologies via training and diverse means.